The Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis

43 460 0
The Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis

Đang tải... (xem toàn văn)

Tài liệu hạn chế xem trước, để xem đầy đủ mời bạn chọn Tải xuống

Thông tin tài liệu

Results Probl Cell Differ (42) P Kaldis: Cell Cycle Regulation DOI 10.1007/002/Published online: 24 February 2006 © Springer-Verlag Berlin Heidelberg 2006 The Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis Jan-Hermen Dannenberg1 (u) · Hein P J te Riele2 (u) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA Jan-Hermen_Dannenberg@dfci.harvard.edu Department of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands h.t.riele@nki.nl Abstract Since its discovery in 1986, as the first tumor suppressor gene, the retinoblastoma gene (Rb) has been extensively studied Numerous biochemical and genetic studies have elucidated in great detail the function of the Rb gene and placed it at the heart of the molecular machinery controlling the cell cycle As more insight was gained into the genetic events required for oncogenic transformation, it became clear that the retinoblastoma gene is connected to biochemical pathways that are dysfunctional in virtually all tumor types Besides regulating the E2F transcription factors, pRb is involved in numerous biological processes such as apoptosis, DNA repair, chromatin modification, and differentiation Further complexity was added to the system with the discovery of p107 and p130, two close homologs of Rb Although the three family members share similar functions, it is becoming clear that these proteins also have unique functions in differentiation and regulation of transcription In contrast to Rb, p107 and p130 are rarely found inactivated in human tumors Yet, evidence is accumulating that these proteins are part of a “tumor-surveillance” mechanism and can suppress tumorigenesis Here we provide an overview of the knowledge obtained from studies involving the retinoblastoma gene family with particular focus on its role in suppressing tumorigenesis Cancer and Genetic Alterations Cancer can be viewed as a disease of the genome Sequentially acquired genetic or epigenetic alterations have progressively provided cells with characteristics that allow uncontrolled proliferation and metastasis (Hanahan and Weinberg 2000) Genes modified in cancer are classified as oncogenes and tumor suppressor genes that have been activated by gain-of-function mutations and inactivated by loss-of-function mutations, respectively The first identified human tumor suppressor gene is the retinoblastoma gene (Rb), which was found to be inactivated in hereditary retinoblastoma, a pediatric eye tumor (Friend et al 1986; Lee et al 1987) Since the discovery of the Rb gene and its product, the pRb protein, numerous studies have shown that most, if not all, human tumors display a deregulated pRb pathway (Sherr 1996) Additionally, many 184 J.-H Dannenberg · H.P.J te Riele biochemical studies have elucidated the function of pRb in controlling cell cycle progression, providing a platform to understand the relevance of pRb loss in development of cancer (reviewed in Weinberg 1995; Hanahan and Weinberg 2000; Harbour and Dean 2000) The molecular cloning of two other Rb-like genes, p107 and p130, defined the retinoblastoma gene family and added to the complexity of cell cycle regulation This chapter will elaborate on the role of the retinoblastoma gene family in cell cycle regulation and tumor suppression The pRb Cell Cycle Control Pathway: Components and the Cancer Connection The retinoblastoma protein, pRb, is a nuclear phosphoprotein that plays a pivotal role in regulation of the cell cycle pRb can exist in a hyper- or hypophosphorylated state, the latter being able to bind and inhibit E2F transcription factors (Dyson 1998) Mitogenic growth factors induce the sequential activation of cell-cycle-dependent kinase complexes, cyclin D/Cdk4-Cdk6 and cyclin E/Cdk2 This results in the phosphorylation and conformational change of pRb allowing the release of E2Fs Derepression and activation of E2F target genes then allows progression from G1 into S-phase of the cell cycle (Lundberg and Weinberg 1998; Harbour et al 1999; Harbour and Dean 2000; Ezhevsky et al 2001) Conversely, growth-inhibitory signals that promote cell cycle arrest, exert their effect by direct down regulation of cyclin protein levels or by inducing members of the INK4A and/or CIP/KIP family of cyclin dependent kinase inhibitors (CKI), resulting in the down-regulation of cyclin/Cdk activity and inhibition of pRb phosphorylation (Ruas and Peters 1998; Sherr and Roberts 1999; Sherr 2001) Sequestration of active E2Fs subsequently results in repression of E2F target genes and ultimately in a cell cycle arrest or exit from the cell cycle (see Fig 1) Thus, pRb can be viewed as a molecular cell cycle switch that is either turned on by growth-inhibiting signals or turned off by growth promoting signals, resulting in cell cycle exit/arrest and cell cycle entry/progression, respectively Inactivation of this proliferation controlling pathway seems to be an essential step in the transition of a normal cell into a cancer cell Inactivation of pRb has been found in many tumor types in humans, including hereditary retinoblastoma and sporadic breast, bladder, prostate and small cell lung carcinomas (Friend et al 1986; Harbour et al 1988; Lee et al 1987; T’Ang et al 1988; Bookstein et al 1990; Horowitz et al 1990) Since pRb/E2F function is controlled at different levels, its deregulation can also occur at different levels Besides loss of pRb function by inactivating mutations or sequestration by viral oncoproteins like adenovirus E1A, simian virus 40 (SV40) large T antigen or human papillomavirus 16 (HPV-16) E7 (DeCaprio et al 1988; Whyte et al 1988; Dyson et al 1989; Ludlow et al 1989), the pRb pathway can be compromised by over-expression of D-type cyclins, mutations rendering Cdk4 The Retinoblastoma Gene Family 185 Fig The p16INK4A -pRb and the p19ARF -p53 pathway involved in cell cycle progression and tumorigenesis Components of these pathways frequently found inactivated (p16INK4A , p19ARF , pRb, p53) or overexpressed (cyclin D, Cdk4) in human cancer are indicated in bold pRb inactivation can also be achieved by viral proteins like SV40-LargeT, adenovirus-E1A or HPV-E7 p53 is inactivated by SV40-LargeT and HPV-E6 We envisage that growth-stimulating or inhibiting signals generally impinge on the activity of cyclin E/Cdk2 We speculate that the pRb pathway regulates the level of cyclin E/Cdk2 while the p53-pathway regulates the cyclin E/Cdk2 activity by controlling the levels of p21CIP1 In the absence of pocket proteins, cyclin E is induced to a level that is refractory to p21CIP1 -mediated inhibition In the absence of p19ARF or p53, p21CIP1 levels are too low to effectively inhibit cyclin E/Cdk2 activity Hence both pathways are required for replicative or oncogene-induced senescence resistant to CKIs, deletion of CKIs or over-expression of E2F transcription factors In accordance with this many human tumors show genetic aberrations affecting the p16INK4A -cyclin D-pRb/E2F pathway: p16INK4A loss of function in melanoma, T-cell leukemias, pancreatic and bladder carcinomas, amplification of cyclin D in breast, oesophagus and head and neck cancer, Cdk4 amplification or mutational activation in melanoma (reviewed in: Sherr 1996; Malumbres and Barbacid 2001; see Fig 1) Regulation of E2F Responsive Genes by pRb E2F transcription factors, named for their activity to mediate transcriptional activation of the adenovirus E2 promoter, recognize and bind together with 186 J.-H Dannenberg · H.P.J te Riele their dimerization partners DP-1 or DP-2 to recognition sequences present in many E2F-responsive genes (Trimarchi and Lees 2001) An intriguing finding was that these target genes are involved in a variety of biological processes such as cell cycle regulation (Rb, p107, E2F1, cyclin A2, cyclin E1, Cdc2), DNA replication (DHFR, MCM, Cdc6, PCNA, DNA polymerase α), DNA repair (RAD54, BARD1), G2/M-checkpoints (CHK1, MAD2, BUB3, SECURIN) and differentiation (EED, EZH2) (Dyson 1998; Harbour and Dean 2000; Ishida et al 2001; Kalma et al 2001; Müller et al 2001; Ren et al 2002), suggesting that pRb/E2F function is not only restricted to regulation of the G1/S transition of cell cycle Whether an E2F target gene is transcriptionally activated or repressed depends on binding of pRb to E2F pRb inhibits the transcriptional activity of E2F by binding to its carboxy-terminal transactivation domain, thereby preventing the interaction of E2F with the basal transcription machinery (Helin et al 1992, 1993; Flemington et al 1993) However, expression of an E2F variant containing the DNA binding motif but not the pRb-binding or transactivation domain or introduction of a competitor plasmid containing multiple E2F binding sites, preventing the binding of E2F and pRb/E2F complexes to cellular promoters, alleviated growth suppression by pRb (Zhang et al 1999; He et al 2000) Active repression of gene transcription thus seems an important mechanism by which pRb arrests the cell cycle pRb bound to E2F recruits chromatin-remodeling proteins that influence the accessibility of a locus for the transcriptional machinery Among these remodeling proteins are histone deacetylases (HDAC1-3), SWI/SNF family proteins (BRG1, Brm), polycomb group proteins (HPC2, Ring1) and histone methyltransferases (SUV39H1, RIZ-1) (Buyse et al 1995; Brehm et al 1998; Luo et al 1998; Magnaghi et al 1998; Lai et al 1999; Dahiya et al 2001; Nielsen et al 2001) Since E2F-1 has been shown to interact with co-activators that have histone acetyltransferase (HAT) activity, which promotes an open chromatin structure and transcriptionally active genomic loci, it seems likely that inhibition of E2F requires HDAC activity, provided by histone deacetylases HDAC1-3 This active repression could result in silencing of a whole locus by recruitment of SUV39H1 and RIZ-1 methyltransferases, allowing tight repression of E2F target genes upon a variety of growth-inhibitory signals Finally, it was shown in a reconstitution transcription assay that chromatin is an essential component for pRb to actively repress transcription, although HDACs did not seem to play a role in this setting (Ross et al 2001) In summary, pRb is able to repress gene transcription by means of direct inhibition of the transcription machinery, direct binding and inhibition of E2F transactivation capacity or by recruiting histone modification proteins It is very likely that the genetic locus, signaling and other (unknown) cellular conditions determine which particular pRb-dependent inhibitory program will be used The Retinoblastoma Gene Family 187 The Retinoblastoma Gene Family 4.1 Rb Gene Family Members The retinoblastoma gene family comprises, besides Rb, the structurally and functionally related Rb-like genes p107 (RBL1) and p130 (RBL2) Whereas the Rb gene was identified as the tumor suppressor gene on the deleted chromosomal region 13q14 in hereditary retinoblastoma, p107 and p130 were cloned by their ability to bind viral oncoproteins, cyclin A and E and Cdk2 p107 is located on human chromosome 20q11, p130 on chromosome 16q12 (Ewen et al 1991; Hannon et al 1993; Li et al 1993; Yeung et al 1993) 4.2 pRb Family Protein Structure The Rb proteins share a high degree of homology within two sub-domains (A and B), which make up the so-called “pocket” domain (Chow and Dean 1996; Lipinski and Jacks 1999; Harbour and Dean 2000; see Fig 2) This region defines the minimal region essential for binding to proteins containing a LXCXE motif, such as the viral oncoproteins adenovirus E1A, SV40 large T antigen and HPV-16 E7, as well as many cellular proteins Although the binding site for LXCXE motif containing proteins is present in the B subdomain, the crystal structure of the pRb A/B pocket bound to the LXCXEcontaining part of HPV-16 E7 revealed that sub-domain A is required for an active conformation of sub-domain B (Lee et al 1998) The functional importance of this region is emphasized by the fact that it is highly conserved between species ranging from C elegans to mammals (Lu and Horvitz 1998) Furthermore, the A/B pocket is sufficient for stable interaction with E2F1 and several transcriptional repressor complexes (Qin et al 1992; Trouche et al 1997; Brehm et al 1998; Magnaghi et al 1998) Studies have shown that the interaction between the A/B pocket region of the pocket protein family and histone modifying enzymes such as histone deacetylase is not direct but is mediated by RBP1 (Lai et al 2001) Outside the pocket domain p107 and p130 are more similar to each other than to pRb C-terminal of the pocket domain in pRb, a region known as the C-domain can bind the proto-oncogene products C-ABL and MDM2, thereby inhibiting C-ABL tyrosine kinase activity and pRb growth suppression functions (Welch et al 1993; Xiao et al 1995) Underscoring the complexity of the interaction between pocket proteins and E2Fs, it was shown that the C-terminal region of pRb contains a E2F1 specific binding site that is sufficient to inhibit E2F1 mediated apoptosis, independent of its transcriptional function (Dick and Dyson 2003) An amino acid sequence identified in sub-domain B of p130 188 J.-H Dannenberg · H.P.J te Riele and named the Loop, was shown to be specifically phosphorylated when cells are in quiescence (Canhoto et al 2000; Hansen et al 2001) This indicates that p107 and p130 harbor regions that are not homologous to each other or to pRb, suggesting that besides similar, each protein also has specific functions 4.3 Similar and Distinct Functions of the pRb Protein Family A similar function of all three pocket proteins is their ability to inhibit E2Fresponsive promoters, recruit HDACs and repress transcription (Zamanian and La 1993; Bremner et al 1995; Starostik et al 1996; Ferreira et al 1998) pRb, p107 and p130 undergo cell-cycle-dependent phosphorylation (Graña et al 1998; Lundberg and Weinberg 1998; Canhoto et al 2000; Hansen et al 2001) Over-expression of each of the pocket proteins results in growth suppression, although not every (tumor) cell-type is equally sensitive to each pRb family member (Zhu et al 1993; Claudio et al 1994; Beijersbergen et al 1995; Ashizawa et al 2001) Besides these similarities, the pRb family members also have unique properties The spacer region that links the A and B domains shows significantly more homology between p107 and p130 than between p107/p130 and pRb This spacer region was shown to contain a p21-like sequence that can recruit and inhibit cyclin A/Cdk2 and cyclin E/Cdk2 kinase complexes Although all pocket proteins are (de)phosphorylated in a cell cycle-dependent manner, pRb and p107 predominantly are phosphorylated during mid-G1 and G1-S phase transition by cyclin D/Cdk4 complexes and subsequently hyperphosphorylated by cyclin E/Cdk2 and cyclin A/Cdk2 (Graña et al 1998; Lundberg and Weinberg 1998) In contrast, p130 is specifically phosphorylated in quiescencent cells in the Loop by Cdk2 and glycogen synthase kinase (Canhoto et al 2000; Hansen et al 2001; Litovchick et al 2004; see Fig 2) Since the phosphorylation sites in the Loop region are largely dispensable for regulation of E2F4 activity it is likely that phosphorylation of these sites are involved in the regulation of p130 specific functions and interactions The difference in phosphorylation sites and kinases involved in the phosophorylation of these sites between p107 and p130 further support specific functions for p107 and p130 (Farkas et al 2002; Litovchick et al 2004) Furthermore, the different retinoblastoma protein family members bind to distinct E2F family members The E2F family of transcription factors consists of six members, E2F1-6 They can be divided into two subgroups on the basis of their activity in regulating transcription E2F1, E2F2 and E2F3 are viewed as “activating” E2Fs, since they are potent transcriptional activators Inactivation of E2f3 impairs the proliferation of mouse embryonic fibroblasts (MEFs) while combined inactivation of E2f1, E2f2 and E2f3 completely blocks proliferation of these cells (Humbert et al 2000; Wu et al 2001), indicating that the members of this The Retinoblastoma Gene Family 189 Fig Protein structure and modifications of pRb, p107 and p130 Within the Rb protein family p107 and p130 share the highest degree of homology (indicated by shaded areas) Within the pocket domain (pocket subdomains A and B and the spacer region) the highest homology between the pRb protein family is found in the A and B subdomains The pocket-domain is responsible for binding to proteins containing LXCXE motifs while the pocket-domain and the C-domain are involved in binding E2F proteins Mdm2 (as well as c-Abl) binds to the C-domain All pocket proteins are subject to phosphorylation (indicated with “P”) although the phosphorylation sites are not all conserved (for detailed information see Canhoto et al 2000; Hansen et al 2001; Farkas et al 2002; Litovchick et al 2004) In p130 the Loop region, a part of the B-pocket subdomain, which is not shared with pRb nor p107, is in particular subject to phosphorylation by GSK3β The Loop region contains phosphorylation sites Besides phosphorylation, pRb is also subject to acetylation (indicated with “Ac”) in its C-domain, a modification that is thought to be involved in the interaction with Mdm2 The size of the pocket proteins is indicated on the right class of E2Fs have overlapping functions and play an essential role in cell cycle progression E2F4, E2F5 and E2F6 form the class of “active repressor” E2Fs Whereas E2F4 and E2F5 execute their function by binding to pocket proteins, E2F6 confers active repression in a pocket protein-independent manner (reviewed in Dyson 1998; Trimarchi and Lees 2001; Cobrinick 2005) Recently, two additional E2F proteins have been identified, E2F7 and E2F8 Similar to E2F6 these proteins seem to repress transcription independently of the pRb protein family (de Bruin et al 2003b; DiStefano et al 2003; Logan et al 2004; Maiti et al 2005) Whereas pRb predominantly binds E2F1, E2F2 and E2F3, p107 and p130 bind specifically E2F4 and E2F5 (Dyson 1998, see Fig 3) The different functionality of the pocket protein/E2F complexes is emphasized by the fact that p107/E2F and p130/E2F complexes act as transcriptional repressors of a set of genes different from that regulated by pRb/E2F complexes (Hurford et al 1997) Upon re-entering the cell cycle and progression through G1 into S phase the levels of p130 protein decrease while p107 protein expression increases, indicating that p107/E2F4 and p130/E2F4 complex formation 190 J.-H Dannenberg · H.P.J te Riele is temporally regulated (Graña 1998) Indeed, each of the pocket proteins appears in complex with E2Fs at different stages of the cell cycle: p130/E2F4 complexes are predominantly found in G0, pRb bound to E2F in G0 and G1, while p107 complexes with E2F in the S-phase of the cell cycle (Dyson 1998) This might reflect the not yet fully understood specific functions of these proteins at these specific stages of the cell cycle 4.4 pRb Family Mediated Regulation of E2F by Cellular Localization Another level of control of the E2F transcriptional activity is added by the cellular compartmentalization of E2F transcription factors E2F1, E2F2 and E2F3 are constitutively nuclear, whereas E2F4 and E2F5 are predominantly cytoplasmic Upon progression from G0 to S-phase, E2F4 and E2F5 are translocated from the nucleus to the cytoplasm (Verona et al 1997) Since E2F4 and E2F5, in contrast to the activating E2Fs, not contain a nuclear localization signal (NLS), other proteins must be involved in their translocation Interaction of these E2Fs with p107 and p130 has been proposed to be required for their nuclear localization (Lindeman et al 1997; Verona et al 1997) As a consequence, p107 and p130 should be able to translocate from the nucleus to the cytoplasm Indeed, besides the presence of nuclear localization signals in the carboxy-terminal region and pocket domain of pRb, p107 and p130 and an additional NLS in the Loop region of p130, a nuclear export signal (NES) is present in the N-terminal region of p130, which is conserved in p107 and pRb (Zacksenhaus et al 1999; Cinti et al 2000; Chestukhin et al 2002) Nucleocytoplasmic shuttling of p130 and p107 might regulate the transcriptional repression activity of E2F4 and/or E2F5 different from phosphorylation mediated disruption of pocket/E2F repression complexes Besides the reliance on these nuclear import and export signals present in the Rb protein family, translocation of p107/E2F repressor complexes to the nucleus has also been observed by usage of other signaling molecules Upon TGF-β signaling cytoplasmic complexes consisting of Smad3 and specifically p107 and E2F4/5 can translocate to the nucleus These complexes subsequently bind to Smad4 and repress Myc transcription, thereby blocking cell cycle progression (Chen et al 2002) 4.5 Regulation of E2F Mediated Gene Expression All three pocket proteins have the ability to repress transcription of E2F responsive genes However, which of the pocket proteins is actually assembled on the promoter of a particular gene seems both gene-specific and conditionspecific Detection of protein complexes associated with promoters of E2Fresponsive genes in vivo by chromatin immuno-precipitation (ChIP) assays, The Retinoblastoma Gene Family 191 Fig Interaction of pRb family members with E2F transcription factors Whereas pRb primarily binds to “activator” E2Fs (E2F1, 2, 3a), p107 and p130 interact with the “repressor” E2Fs (E2F4 and E2F5) E2F6, E2F7, E2F8 are involved in pRb family-independent repression of gene transcription revealed that in serum-starved G0 cells these promoters were predominantly occupied by E2F4 and p130 Upon re-entry into the cell cycle these repressive complexes were replaced by activating E2F1, E2F2 and E2F3 In these assays, pRb could not be detected on promoters of a selected group of E2Ftarget genes in cycling cells (Takahashi et al 2000; Wells et al 2000; Dahiya et al 2001) However, the observation that cyclin E is de-repressed in Rb–/– MEFs and not in p107 –/– p130–/– MEFs, suggests that pRb and not p107 and p130, is primarily involved in suppression of cyclin E transcription (Herrera et al 1996; Hurford et al 1997) Indeed, pRb could be detected on the promoters of cyclin E as well as cyclin A upon ectopic expression of p16INK4A or serum withdrawal indicating that pRb/E2F mediated repression of E2Fresponsive genes may play a role in establishing cell cycle arrest (Dahiya et al 2001; Morrison et al 2002) This view was further supported by the observation that in senescent cells pRb, together with heterochromatin proteins, could be found in senescence associated heterochromatin foci (SAHF) that included E2F-responsive promoters (Narita et al 2003) However, it should be noted that under growth inhibiting conditions such as cell-cell contact, serum deprivation and p16INK4A over-expression, p130 and E2F4 can be found on the promoters of a common set of genes Surprisingly, most of these genes are not involved in cell cycle regulation but in mitochondrial biogenesis and metabolism (Cam et al 2004) Furthermore, many recently identified E2F-responsive genes were de-repressed in p107 –/– p130–/– MEFs, suggesting that p107 and p130 bound to E2F4/E2F5 are important repressors, and 192 J.-H Dannenberg · H.P.J te Riele that pRb/E2F complexes cannot compensate in repressing the transcription of these genes (Ren et al 2002) Strikingly, MEFs deficient for E2F4 and E2F5 did not show de-repression of E2F-responsive genes, suggesting that p107 and p130 can repress transcription in an E2F4/5 independent fashion A specific function was found for p130 in the regulation of neuronal survival and death by repressing pro-apoptotic genes through recruitment of histone modifiers such as HDAC1 and Suv39H1 (Liu et al 2005) The observation that only p107 together with E2F4/5 and Smad proteins was found on the promoter of c-Myc upon TGFβ-signaling underscores the specific functions of the different pRb gene family members in repression of specific genes upon activation of specific signaling pathways (Chen et al 2002) 4.6 The pRb Family and the Cellular Response Towards Growth-Inhibitory Signals Many growth-inhibitory conditions such as lack of growth factors, cell-cell contact, DNA damage, lack of anchorage and differentiation are accompanied by the induction of cyclin dependent kinase inhibitors and result in the accumulation of hypophosphorylated pocket proteins and (temporal or definitive) cell cycle arrest This led to the model that pocket proteins are mediators of growth-inhibitory signals (Weinberg 1995) Indeed, analysis of mouse embryonic fibroblasts deficient for combinations of pocket proteins revealed that the Rb gene family members have overlapping roles in controlling cell cycle exit upon growth-inhibiting signals Only ablation of all pocket proteins fully alleviated a cell cycle arrest upon serum withdrawal, cell-cell contact inhibition, DNA damage, differentiation and prolonged culturing (Dannenberg et al 2000; Sage et al 2000) The functional redundancy of the pocket proteins is also manifested by the upregulation of p107 and to a lesser extent of p130 in pRb-deficient cells (Hurford et al 1997; Dannenberg et al 2000, 2004; MacPherson et al 2004) Indeed, MEFs lacking either pRb and p107 or pRb and p130 are more resistant to growth inhibitory stimuli than MEFs lacking only pRb (Dannenberg et al 2000, 2004, Sage et al 2000; Peeper et al 2001) Interestingly, whereas MEFs deficient for either pRb or p107 require serum to enter S-phase, MEFs lacking both pRb and p107 lack this serum requirement In contrast, Rb/p107 deficient MEFs still require cell anchorage in order to progress into S-phase, suggesting that pRb and p107 constitute the serum restriction point whereas the cell-anchorage restriction point extends beyond these retinoblastoma gene family members (Gad et al 2004) p16INK4A requires functional pRb to impose a G1 arrest (Lukas et al 1995; Medema 1995) Unexpectedly, MEFs lacking either p107 and p130 or E2F4 and E2F5, were also refractory to p16INK4A -induced G1 arrest (Bruce et al 2000; Gaubatz et al 2000), suggesting that p16INK4A -mediated growth arrest requires repression of specific genes by p107 and p130 Alternatively, the pocket protein/E2F complexes may target the same set of genes, but the total The Retinoblastoma Gene Family 211 conditions such as cell culture stress, serum starvation, contact inhibition, oncogene activation and differentiation These observations provide an understanding for the almost universal inactivation of the p16-cyclin D/CdkpRb-E2F pathway across tumor types Loss of function of pRb will not only lead to loss of cell cycle regulation under growth restricting conditions (e.g differentiation), but also create an environment that favors the acquisition of additional transforming mutations through increased cell turnover or increased chromosomal instability Tissue specific tumor development due to inactivation of the Rb gene family may reflect its role beyond regulation of E2F such as activation of tissue specific differentiation inducers in differentiating cells Furthermore, direct or indirect inactivation of p107 or p130 function may be required on top of pRb deficiency as indicated by the tumor prone phenotype of chimeric mice lacking either pRb and p107 or Rb and p130 Thus, the oncogenic potential of loss of Rb is likely to be decided by the expression of each of the Rb family members and the role these family members play in the differentiation of the cell type involved Future research will unquestionably reveal more specific functions for each of the pRb protein family members in biological processes relevant to tumor suppression Ultimately, this knowledge will help to define targets for therapeutic intervention Acknowledgements We thank our colleagues Floris Foijer, Jacob Hansen, René Medema, Daniel Peeper, Rob Wolthuis and many others for helpful discussions related to this chapter Work in the Te Riele lab is supported by grants from the Dutch Cancer Society, the European Commission and the Netherlands Genomics Initiative References Ashizawa S, Nishizawa H, Yamada M, Higashi H, Kondo T, Ozawa H, Kakita A, Hatakeyama M (2001) Collective inhibition of pRB family proteins by phosphorylation in cells with p16INK4A loss or cyclin E overexpression J Biol Chem 276:11362– 11370 Balsitis SJ, Sage J, Duensing S, Munger K, Jacks T, Lambert PF (2003) Recapitulation of the effects of the human papillomavirus type 16 E7 oncogene on mouse epithelium by somatic Rb deletion and detection of pRb-independent effects of E7 in vivo Mol Cell Biol 23:9094–9103 Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH (1998) p14ARF links the tumour suppressors RB and p53 Nature 395:124–125 Beijersbergen RL, Carlée L, Kerkhoven RM, Bernards R (1995) Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes Genes Dev 9:1340–1353 Bellan C, De Falco G, Tosi GM, Lazzi S, Ferrari F, Mobini G, Bartolomei S, Toti P, Mangiavacchi P, Cevenini G (2002) Missing expression of pRb2/p130 in human retinoblastomas is associated with reduced apoptosis and lesser differentiation Invest Ophthalmol Vis Sci 43:3602–3608 Berns K, Martins C, Dannenberg JH, Berns A, Te Riele H, Bernards R (2000) p27kip independent cell cycle regulation by MYC Oncogene 19:4822–4827 212 J.-H Dannenberg · H.P.J te Riele Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong, W, Johnson, BE, Golub TR, Sugarbaket DJ, Meyerson M (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinomas subclasses Proc Natl Acad Sci USA 98:13790–13795 Bookstein R, Rio P, Madreperla SA, Hong F, Allred C, Grizzle WE, Lee WH (1990) Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma Proc Natl Acad Sci USA 87:7762–7766 Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T (1998) Retinoblastoma protein recruits histone deacytelase to repress transcription Nature 391:597– 601 Bremner R, Cohen BL, Sopta M, Hamel PA, Ingles CJ, Gallie BL, Phillips RA (1995) Direct transcriptional repression by pRB and its reversal by specific cyclins Mol Cell Biol 15:3256–3265 Bremner R, Du DC, Connolly-Wilson MJ, Bridge P, Ahmad KF, Mostachfi H, Rushlow D, Dunn JM, Gallie BL (1997) Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma Am J Hum Genet 61:556–570 Bruce JL, Hurford RK, Classon M, Koh J, Dyson N (2000) Requirements for cell cycle arrest by p16INK4A Mol Cell 6:737–742 de Bruin A, Wu L, Saavedra HI, Wilson P, Yang Y, Rosol TJ, Weinstein M, Robinson ML, Leone G (2003a) Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice Proc Natl Acad Sci USA 100:6546–6551 de Bruin A, Maiti B, Jakoi L, Timmers C, Buerki R, Leone G (2003b) Identification and characterization of E2F7, a novel mammalian E2F family member capable of blocking cellular proliferation J Biol Chem 278:42041–42049 Buyse IM, Shao G, Huang S (1995) The retinoblastoma protein binds to RIZ, a zinc finger protein that shares an epitope with the adenovirus E1A protein Proc Natl Acad Sci USA 92:4467–4471 Cam H, Balciunaite E, Blais A, Spektor A, Scarpulla RC, Young R, Kluger Y, Dynlacht BD (2004) A common set of gene regulatory networks links metabolism and growth inhibition Mol Cell 16:399–411 Campisi J (1997) The biology of replicative senescence Eur J Cancer 33:703–709 Canhoto AJ, Chestukhin A, Litovchick L, DeCaprio JA (2000) Phosphorylation of the retinoblastoma-related protein p130 in growth-arrested cells Oncogene 19:5116–5122 Carnero A, Hudson JD, Price CM, Beach DH (2000) p16INK4A and p19ARF act in overlapping pathways in cellular immortalization Nat Cell Biol 2:148–155 Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB (2001) Acetylation control of the retinoblastoma tumour-suppressor protein Nat Cell Biol 3:667– 674 Chao HHA, Buchmann AM, DeCaprio JA (2000) Loss of p19ARF eliminates the requirement for the pRB-binding motif in simian virus 40 large T antigen-mediated transformation Mol Cell Biol 20:7624–7633 Chen CR, Kang Y, Siegel PM, Massague J (2002) E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-Myc repression Cell 110:19–32 Chen D, Gallie BL, Squire JA (2001) Minimal regions of chromosomal imbalance in retinoblastoma detected by comparative genomic hybridization Cancer Genetics and Cytogenetics 129:57–63 Chen D, Livne-bar I, Vanderluit JL, Slack RS, Agochiya M, Bremner R (2004) Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically deathresistant cell-of-origin in retinoblastoma Cancer Cell 5:539–551 The Retinoblastoma Gene Family 213 Cheng L, Rossi F, Fang W, Mori T, Cobrinik D (2000) Cdk2-dependent phosphorylation and functional inactivation of the pRB-related protein in pRB(–), p16INK4A (+) tumor cells J Biol Chem 275:30317–30325 Chestukhin A, Litovchick L, Rudich K, DeCaprio JA (2002) Nucleocytoplasmic shuttling of p130/RBL2: novel regulatory mechanism Mol Cell Biol 22:453–468 Chow KN, Dean DC (1996) Domains A and B in the Rb pocket interact to form a transcriptional repressor motif Mol Cell Biol 16:4862–4868 Cinti C, Claudio PP, Howard CM, Neri LM, Fu Y, Leoncini L, Tosi GM, Maraldi NM, Giordano A (2000) Genetic alterations disrupting the nuclear localization of the retinoblastoma-related gene RB2/p130 in human tumor cell lines and primary tumors Cancer Res 60:383–389 Clarke AR, Robanus Maandag E, Van Roon M, Van der Lugt NMT, Van der Valk M, Hooper ML, Berns A, Te Riele H (1992) Requirement for a functional Rb-1 gene in murine development Nature 359:328–330 Claudio PP, Howard CM, Baldi A, De Luca A, Fu Y, Condorelli G, Sun Y, Colburn N, Calabretta B, Giordano A (1994) p130/RB2 has growth suppressive properties similar to yet distinctive from those of retinoblastoma family members pRB and p107 Cancer Res 54:5556–5560 Claudio PP, Howard CM, Pacilio C, Cinti C, Romano G, Minimo C, Maraldi NM, Minna JD, Gelbert L, Leoncini L, Tosi GM, Hicheli P, Caputi Giordano GG, Giordano A (2000a) Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer Cancer Res 60:372–382 Claudio PP, Howard CM, Fu Y, Cinti C, Califano L, Micheli P, Mercer EW, Caputi M, Giordano A (2000b) Mutations in the retinoblastoma-related gene RB2/p130 in primary nasopharyngeal carcinoma Cancer Res 60:8–12 Cobrinik D (2005) Pocket proteins and cell cycle control Oncogene 24:2796–2809 Cobrinik D, Lee MH, Hannon G, Mulligan G, Bronson RT, Dyson N, Harlow E, Beach D, Weinberg RA, Jacks T (1996) Shared role of the pRB-related p130 and p107 proteins in limb development Genes Dev 10:1633–1644 Dannenberg JH, Rossum A van, Schuijff L, Te Riele H (2000) Ablation of the retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth restricting conditions Genes Dev 14:3051–3064 Dannenberg JH, Schuijff L, Dekker M, van der Valk M, Te Riele H (2004) Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130 Genes Dev 18:2952–2962 Dahiya A, Wong S, Gonzalo S, Gavin M, Dean DC (2001) Linking the Rb and Polycomb pathways Mol Cell 8:557–568 DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee W-H, Marsilio E, Paucha E, Livingston DM (1988) SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene Cell 54:275–283 DeGregory J, Leone G, Miron A, Jakoi L, Nevins JR (1997) Distinct roles for E2F proteins in cell growth control apoptosis Proc Natl Acad Sci USA 94:7245–7250 Demers GW, Foster SA, Halbert CL, Galloway DA (1994) Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7 Proc Natl Acad Sci USA 91:4382–4386 De Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW (1998) E1A signaling to p53 involves the p19ARF tumor suppressor Genes Dev 12:2434–2442 214 J.-H Dannenberg · H.P.J te Riele Dick FA, Dyson N (2003) pRB contains an E2F1 specific binding domain that allows E2F-1 induced apoptosis to be regulated separately from other E2F activities Mol Cell 12:639–649 Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C, Pandolfi PP (2001) Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse Nat Genet 27:222–224 Di Stefano L, Jensen MR, Helin K (2003) E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes EMBO J 22:6289–6298 Donehower LA, Harvey M, Slagte BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours Nature 356:215–221 Donovan SL, Dyer MA (2004) Developmental defects in Rb-deficient retinae Vision Res 44:3323–3333 Dubs-Poterszman MC Tocque B, Wasylyk B (1995) MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest Oncogene 11:2445–2449 Dyson N (1998) The regulation of E2F by pRB-family proteins Genes Dev 12:2245–2262 Dyson N, Howley PM, Munger K, Harlow E (1989) The human papillomavirus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product Science 243:934– 936 Ebenhard D, Busslinger M (1999) The partial homeodomain of the transcription factor Pax-5 (BSAP) is an interaction motif for the retinoblastoma and TATA-binding proteins Cancer Res 59:1716s–1725s Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL (1999) Disruption of the ARFMdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis Genes Dev 13:2658–2669 Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters C, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein Cell 69:119–128 Ewen ME, Xing YG, Lawrence JB, Livingston DM (1991) Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein Cell 66:1155–1164 Ezhevsky SA, Ho A, Becker-Hapak M, Davis PK, Dowdy SF (2001) Differential regulation of retinoblastoma tumor suppressor protein by G1 cyclin-dependent kinase complexes in vivo Mol Cell Biol 21:4773–4784 Farkas T, Hansen K, Holm K, Lukas J, Bartek J (2002) Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4 J Biol Chem 277:26741–26752 Ferguson KL, Vanderluit JL, Hebert JM, McIntosh WC, Tibbo E, MacLaurin JG, Park DS, Wallace VA, Vooijs M, McConnell SK, Slack RS (2002) Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development EMBO J 21:3337–3346 Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D (1998) The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylases Proc Natl Acad Sci USA 95:10493–10481 Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koresky A, Varmus HE (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes Genes Dev 15:3249–3262 Flesken-Nikitin A, Choi KC, Eng JP, Shmidt EN, Nikitin AY (2003) Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium Cancer Res 63:3459–3463 The Retinoblastoma Gene Family 215 Flemington EK, Speck SH, Kaelin WG Jr (1993) E2F-1-meidated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product Proc Natl Acad Sci USA 90:6914–6918 Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Drya TP (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma Nature 323:643–646 Friend SH, Horowitz JM, Gerber MR, Wang XF, Bogenmann E, Lif P, Weinberg RA (1987) Deletion of a DNA sequence in retinoblastomas and mesenchymal tumours: organization of the sequence and its encoded protein Proc Natl Acad Sci USA 84:9059–9063 Gad A, Thullberg M, Dannenberg JH, Te Riele H, Stromblad S (2004) Retinoblastoma susceptibility gene product (pRb) and p107 functionally separate the requirements for serum and anchorage in the cell cycle G1-phase J Biol Chem 279:13640–13644 Gallie BL, Campbell C, Devlin H, Duckett A, Squire JA (1999) Developmental basis of retinal-specific induction of cancer by RB mutation Cancer Res 59:1731s–1735s Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach van de Rijn M, Rosen GD, Perou CM, Whyte RI, Altman RB, Brown PO, Botstein D, Petersen I (2001) Diversity of gene expression in adenocarcinomas of the lung Proc Natl Acad Sci USA 98:13784–13789 Gaubatz S, Lindeman GJ, Ishida S, Jakoi L, Nevins JR, Livingston DM, Rempel RE (2000) E4F4 and E2F5 play and essential role in pocket protein-mediated G1 control Mol Cell 6:729–735 Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AHFM, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T, Blasco M (2005) Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin Nat Cell Biol 7:420–428 Graña X, Garriga J, Mayol X (1998) Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth Oncogene 17:3365–3383 Gray SG, Guo X (2001) Correspondence re: Claudio PP et al Mutation in the retinoblastoma-related gene RB2/p130 in primary nasopharyngeal carcinoma Cancer Res 60:8–12 Groth A, Weber JD, Willumsen BM, Sherr CJ, Roussel MF (2000) Oncogenic Ras induces p19ARF and growth arrest in mouse embryo fibroblasts lacking p21CIP1 and p27KIP1 without activating cyclin D-dependent kinases J Biol Chem 275:27473–27480 Guo Z, Yikang S, Yoshida H, Mak TW, Zacksenhaus E (2001) Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis Cancer Res 61:8395–8400 Hanahan D, Weinberg RA (2000) The hallmarks of cancer Cell 100:57–70 Hannon GJ, Demetrick D, Beach D (1993) Isolation of the Rb-related p130 through its interaction with Cdk2 and cyclins Genes Dev 7:2378–2391 Hansen K, Farkas T, Lukas J, Holm K, Rönnstrand L, Bartek J (2001) Phosphorylationdependent and -independent functions of p130 cooperate to evoke a sustained G1 block EMBO J 20:422–432 Harbour JW, Dean DC (2000) The Rb/E2F pathway: expanding roles and emerging paradigms Genes Dev 14:2393–2409 Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ (1988) Abnormalities in structure and expression of the human retinoblastoma gene in SCLC Science 241:353–357 Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC (1999) Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1 Cell 98:859–869 216 J.-H Dannenberg · H.P.J te Riele Harvey DM, Levine AJ (1991) p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine fibroblasts Genes Dev 5:2375–2385 Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A, Donehower LA (1993) In vitro growth characteristics of embryo fibroblasts isolated of p53-deficient mice Oncogene 8:2457–2467 Harvey M, Vogel H, Lee EY, Bradley A, Donehower LA (1995) Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin Cancer Res 55:1146–1151 Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains Exp Cell Res 25:585–621 He S, Cook BL, Deverman BE, Wehe U, Zhang F, Prachand V, Zheng J, Weintraub SJ (2000) E2F is required to prevent inappropriate S-phase entry of mammalian cells Mol Cell Biol 20:363–371 Helin K, Lees JA, Vidal M, Dyson N, Harlow E, Fattaey A (1992) A cDNA encoding a pRBbinding protein with properties of the transcription factor E2F Cell 70:337–350 Helin K, Harlow E, Fattaey A (1993) Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein Mol Cell Biol 13:6501–6508 Helin K, Holm K, Niebuhr A, Eiberg H, Tommerup N, Hougaard S, Poulse HS, SpangThomsen M, Norgaard P (1997) Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma Proc Natl Acad Sci USA 94:6933–6938 Hernando E, Nahle Z, Juan G, Diaz-Rodrigriguez E, Alaminos Hermann M, Michel L, Mittal V, Gerald W, Benezra R, Lowe SW, Cordon-Cardo C (2004) Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control Nature 430:797–802 Herrera RE, Sah VP, Williams BO, Weinberg RA, Jacks T (1996) Altered cell cycle kinetics, gene expression and G1 restriction point regulation in Rb-deficient fibroblasts Mol Cell Biol 16:2402–2407 Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW, Kaye FJ, Minna JD, Drya TP, Weinberg RA (1990) Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells Proc Natl Acad Sci USA 87:2775–2779 Hsieh JK, Chan FS, O’Connor DJ, Mittnacht S, Zhong S, Lu X (1999) RB regulates the stability and the apoptotic function of p53 and MDM2 Mol Cell 3:181–193 Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY (1994) Heterozygous Rb-1 delta 20/+ mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance Oncogene 9:1021–1027 Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA (2000) E2F3 is critical for normal cellular proliferation Genes Dev 14:690–703 Hurford RK, Cobrinik D, Lee MH, Dyson N (1997) pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes Genes Dev 11:1447– 1463 Ichimura K, Hanafusa H, Takimoto H, Ohgma Y, Akagi T, Shimizu K (2000) Structure of the human retinoblastoma-related p107 gene and its intragenic deletion in a B-cell lymphoma cell line Gene 251:37–43 Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin WG Jr (2000) Role for the p53 homologue p73 in E2F-1 induced apoptosis Nature 407:642–645 Ishida S, Huang E, Zuzan H, Spang R, Leone G, West M, Nevins JR (2001) Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis Mol Cell Biol 21:4684–4699 Ito T, Udak N, Yazawa T, Okudela K, Hayashi H, Sudo T, Guillemot F, Kageyama R, Kitamura H (2000) Basic helix-loop-helix transcription factors regulate the neuro- The Retinoblastoma Gene Family 217 endocrine differentiation of fetal mouse pulmonary epithelium Development 127:3913–3921 Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse Nature 359:295–300 Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, Weinberg RA (1994) Tumor spectrum analysis in p53 mutant mice Curr Biol 4:1–7 Jen Y, Manova K, Benezra R (1996) Expression patterns of Id1, Id2 and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis Dev Dyn 207:235–252 Kalma Y, Marash L, Lamed Y, Ginsberg D (2001) Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2 Oncogene 20:1379–1387 Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH (1994) A cell cycle regulator involved in genesis of many tumor types Science 264:436–440 Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4A locus mediated by the alternative reading frame product p19ARF Cell 91:649–659 Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2 Proc Natl Acad Sci USA 95:8292–8287 Kondo T, Higashi H, Nishizawa H, Ishikawa S, Ashizawa S, Yamada M, Makita Z, Koike T, Hatakeyama M (2001) Involvement of pRB-related p107 protein in the inhibition of Sphase progression in response to genotoxic stress J Biol Chem 276:17559–17567 Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A (2001) Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice Nature 413:83–86 Lai A, Lee JM, Yang WM, DeCaprio JA, Kaelin Jr WG, Seto E, Branton PE (1999) RBP1 recruits both histone deacetylases-dependent and -independent repression activities to retinoblastoma family proteins Mol Cell Biol 19:6632–6641 Lai A, Kennedy BK, Barbie DA, Bertos NR, Yang JX, Theberge MC, Tsai SC, Seto E, Zhang Y, Kuzmichev A, Lane WS, Reinberg D, Harlow E, Branton PE (2001) RBP1 Recruits the mSin3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest Mol Cell Biol 21:2918–2932 Lasorella A, Noseda M, Beyna M, Iavarone A (2000) Id2 is a retinoblastoma protein target and mediates signaling by Myc oncoproteins Nature 407:592–598 LeCouter J, Kablar B, Hardy WR, Ying C, Megeney LA, May LL, Rudnicki MA (1998a) Strain-dependent myeloid hyperplasia, growth deficiency and accelerated cell cycle in mice lacking the Rb-related p107 gene Mol Cell Biol 18:7455–7465 LeCouter J, Kablar B, Whyte PFM Ying C, Rudnicki MA (1998b) Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene Development 125:4669–4679 Lee EY, Cam H, Ziebold U, Rayman JB, Lees JA, Dynlacht BD (2002) E2F4 loss suppresses tumorigenesis in Rb mutant mice Cancer Cell 2:463–472 Lee EYHP, To H, Shew JY, Bookstein R, Scully P, Lee WH (1987) Inactivation of the retinoblastoma susceptibility gene in human breast cancers Science 241:218–221 Lee EYHP, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis Nature 359:288–294 Lee JO, Russo AA, Pavlitch NP (1998) Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7 Nature 391:859–865 218 J.-H Dannenberg · H.P.J te Riele Lee MH, Williams BO, Mulligan G, Mukai S, Bronson RT, Dyson N, Harlow E, Jacks T (1996) Targeted disruption of p107: functional overlap between p107 and Rb Genes Dev 10:1621–1632 Li Y, Graham C, Lacy S, Duncan AMV, Whyte P (1993) The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E Genes Dev 7:2366–2377 Lindeman GJ, Gaubatz S, Livingston DM, Ginsberg D (1997) The subcellular localization of E2F-4 is cell-cycle dependent Proc Natl Acad Sci USA 94:5095–5100 Lipinski MM, Jacks T (1999) The retinoblastoma gene family in differentiation and development Oncogene 18:7873–7882 Linnoila IR, Zhao B, DeMayo JL, Nelkin BD, Baylin SB, DeMayo FJ, Ball DW (2000) Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice Cancer Res 60:4005–4009 Lissy NA, Davis PK, Irwin M, Kaelin WG, Dowdy SF (2000) A common E2F-1 and p73 pathway mediates cell death induced by TCR activation Nature 407:642–645 Litovchick L, Chestukhin A, DeCaprio J (2004) Glycogen synthase kinase phosphorylates RBL2/p130 during quiescence Mol Cell Biol 24:8970–8990 Liu DX, Nath N, Chellappan SP, Greene LA (2005) Regulation of neuron survival and death by p130 and associated chromatin modifiers Genes Dev 19:719–732 Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M, Land H (1997) Cooperating oncogenes converge to regulate cyclin/Cdk complexes Genes Dev 11:663–677 Logan N, Delavaine L, Graham A, Reilly C, Wilson J, Brummelkamp TR, Hijmans EM, Bernards R, La Thangue NB (2004) E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains Oncogene 23:5138–5150 Lowe SW, Ruley HE (1993) Stabilization of the p53 tumor suppressor is induced by adenovirus E1A and accompanies apoptosis Genes Dev 7:535–545 Loughran O, La Thangue NB (2000) Apoptotic and growth-promoting activity of E2F modulated by MDM2 Mol Cell Biol 20:2186–2197 Lu X, Horvitz HR (1998) lin-35 and lin-53, two genes that antagonize a C elegans Ras pathway, encode proteins similar to Rb and its binding protein RbAp48 Cell 95:981–991 Ludlow JW, DeCaprio JA, Huang CM, Lee WH, Paucha E, Livingston DM (1989) SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family Cell 56:57–65 Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J (1995) Retinoblastoma protein-dependent cell cycle inhibition by the tumor suppressor p16 Nature 375:503–506 Lundberg AS, Weinberg RA (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cylin-Cdk complexes Mol Cell Biol 18:753–761 Luo RX, Postigo AA, Dean DC (1998) Rb interacts with histone deacytelase to repress transcription Cell 92:463–473 MacLellan WR, Garcia A, Oh H, Frenkel P, Jordan MC, Roos KP, Schneider MD (2005) Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb Mol Cell Biol 25:2486–2497 Macleod KF, Hu Y, Jacks T (1996) Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system EMBO J 15:6178–6188 MacPherson D, Sage J, Crowley D, Trumpp A, Bronson RT, Jacks T (2003) Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system Mol Cell Biol 23:1044–1053 The Retinoblastoma Gene Family 219 MacPherson D, Sage J, Kim T, Ho D, McLaughlin ME, Jacks T (2004) Cell type-specific effects of Rb deletion in the murine retina Genes Dev 18:1681–1694 Maddison LA, Sutherland BW, Barrios RJ, Greenberg NM (2004) Conditional deletion of Rb causes early stage prostate cancer Cancer Res 64:6018–6025 Magnaghi JL, Groisman R, Naguibneva I, Robin P, Lorain S, Le VJ, Troalen F, Trouche D, Harel BA (1998) Retinoblastoma protein represses transcription by recruiting a histone deacytelase Nature 391:601–605 Mairal A, Pinglier E, Gilbert E, Peter M, Validire P, Desjardins L, Doz F, Aurias A, Couturier J (2000) Detection of chromosome imbalances in retinoblastoma by parallel karyotype and CGH analyses Genes Chrom Cancer 28:370–379 Maiti B, Li J, de Bruin A, Gordon F, Timmers C, Opavsky R, Patil K, Tuttle J, Cleghorn W, Leone G (2005) Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation J Biol Chem 280:18211– 18220 Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer Nature Reviews Cancer 1:222–231 Martelli F, Hamilto T, Silver DP, Sharpless NE, Bardeesy N, Rokas M, DePinho RA, Livingston DM, Grossman SR (2001) p19ARF targets certain E2F species for degradation Proc Natl Acad Sci USA 98:4455–4460 Martin K, Trouche D, Hagemeier D, Sorensen TS, La Thangue NB, Kouzarides T (1995) Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein Nature 375:691–694 Marguardt T, Ashery-Padan R, Andrejewski N, Scardigli F, Guillemot F, Gruss P (2001) Pax6 is required for the multipotent state of retinal progenitor cells Cell 105:43–55 Marino S, Vooijs M, Van Der Gulden H, Jonkers J, Berns A (2000) Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum Genes Dev 14:994–1004 Marino S, Hoogervoorst D, Brandner S, Berns A (2003) Rb and p107 are required for normal cerebellar development and granule cell survival but not for Purkinje cell persistence Development 130:3359–3368 Mathon NF, Malcolm DS, Harrisingh MC, Cheng L, Lloyd C (2001) Lack of replicative senescence in normal rodent glia Science 291:872–875 Mayhew CN, Bosco EE, Fox SR, Okaya T, Tarapore P, Schwemberger SJ, Babcock GF, Lentsch AB, Fukasawa K, Knudsen ES (2005) Liver-specific pRB loss results in ectopic cell cycle entry and aberrant ploidy Cancer Res 65:4568–4577 Medema RH, Herrera RE, Lam F, Weinberg RA (1995) Growth suppression by the p16Ink4a requires functional retinoblastoma protein Proc Natl Acad Sci USA 92:6289–6293 Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A (2003) Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model Cancer Cell 3:181–189 Modestou M, Antich VP, Korgaonkar C, Eapen A, Quelle DE (2001) The alternative reading frame tumor suppressor inhibits growth through p21-dependent and p21independent pathways Cancer Res 61:3145–3150 Modi S, Kubo A, Oie H, Coxon AB, Rehmatulla A, Kaye FJ (2000) Protein expression of the RB-related gene family and SV40 large T antigen in mesothelioma and lung cancer Oncogene 19:4632–4639 Moll AC, Imhof SM, Bouter LM, Tan KE (1997) Second primary tumors in patients with retinoblastoma A review of the literature Opthalmic Genet 1:27–34 Morgenbesser SD, Williams BO, Jacks T, DePinho RA (1994) p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens Nature 371:72–74 220 J.-H Dannenberg · H.P.J te Riele Moroni MC, Hickman ES, Denchi EL, Carprara G, Colli E, Cecconi F, Muller H, Helin K (2001) Apaf-1 is a transcriptional target for E2F and p53 Nat Cell Biol 3:552–558 Morrison AJ, Sardet C, Herrera RE (2002) Retinoblastoma protein transcriptional repression through histone deacetylation of a single nucleosome Mol Cell Biol 22:856–865 Morrow E, Furukawa T, Lee JE, Cepko CL (1999) NeuroD regulates multiple functions in the developing neural retina in rodent Development 126:23–36 Müller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassili E, Prosperini E, Vigo E, Oliner JD, Helin K (2001) E2Fs regulate the expression of genes involved in differentiation, development, proliferation and apoptosis Genes Dev 15:267–285 Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence Cell 113:703–716 Nguyen DX, Baglia LA, Huang SM, Baker CM, McCance JD (2004) Acetylation regulates the differentiation-specific functions of the retinoblastoma protein EMBO J 23:1609–1618 Nielsen SJ, Schneider R, Bauer U-M, Bannister AJ, Morrison A, O’Caroll D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T (2001) Rb targets histone H3 methylation and HP1 to promoters Nature 412:561–565 Nobori T, Miura K, Wu DJ, Lois A, Tkabayashi K, Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers Nature 368:753–756 Nork TM, Schwartz TL, Doshi HM, Millecchia LL (1995) Retinoblastoma: Cell of origin Arch Ophthalmol 113:791–802 Nork TM, Poulsen GL, Millechia LL, Jantz RG, Nickells RW (1997) p53 regulates apoptosis in human retinoblastoma Arch Opthalmol 115:213–219 Novitch BG, Mulligan GJ, Jacks T, Lassar AB (1996) Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle J Cell Biol 135:441–456 Novitch BG, Spicer DB, Kim PS, Cheung WL, Lassar AB (1999) pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation Curr Biol 9:449–459 Pan H, Yin C, Dyson N, Harlow E, Yamasaki L, Van Dyke (1998) A key role for E2F1 in p53-dependent apoptosis and cell division within developing tumors Mol Cell 2:283–292 Palmero I, Pantoja C, Serrano M (1998) p19ARF links the tumour suppressor p53 to Ras Nature 395:125–126 Pantoja C, Serrano M (1999) Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras Oncogene 18:4974–4982 Paramio JM, Navarro M, Segrelles C, Gomez-Casero E, Jorcano JL (1999) PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein Oncogene 18:7462–7468 Pearse AGE, Polak JM (1978) The diffuse neuroendocrine system and the APUD concept In: Bloom SR (ed) Gut hormones Churchill Livingstone, London New York, pp 33–39 Peeper DS, Dannenberg JH, Douma S, Te Riele H, Bernards R (2001) Escape from premature senescence is not sufficient for oncogenic transformation Nat Cell Biol 3:198–203 Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA (1998) The Ink4a tumor suppressor gene product, p19ARF , interacts with MDM2 and neutralizes MDM2’s inhibition of p53 Cell 92:713–723 The Retinoblastoma Gene Family 221 Potluri VR, Helson L, Ellsworth RM, Reid T, Gilbert F (1986) Chromosomal abnormalities in human retinoblastoma: a review Cancer 58:663–671 Qin XQ, Chittenden T, Livingston DM, Kaelin WG Jr (1992) Identification of a growth suppression domain within the retinoblastoma gene product Genes Dev 6:953–964 Quelle DE, Zindy F, Ashmun RA, Sherr CJ (1995) Alternative reading frames of the INK4A tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest Cell 83:993–1000 Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW, Wright WE (2001) Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions Genes Dev 15:398–403 Radfar A, Unnikrishnan I, Lee HW, DePinho RA, Rosenberg N (1998) p19Arf induces p53dependent apoptosis during abelson virus-mediated pre-B cell transformation Proc Natl Acad Sci USA 95:13194–13197 Randle DH, Zindy F, Sherr CJ, Roussel MF (2001) Differential effects of p19Arf and p16Ink4a loss on senescence of murine bone marrow-derived preB cells and macrophages Proc Natl Acad Sci USA 98:9654–9659 Rane GS, Cosenza SC, Mettus RV, Reddy EP (2002) Germ line transmission of the Cdk4R24C mutation facilitates tumorigenesis and escape from cellular senescence Mol Cell Biol 22:644–656 Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht D (2002) E2F integrates cell cycle progression with DNA repair, replication, and G2 /M-checkpoints Genes Dev 16:245–256 Rittling SR, Denhardt DT (1992) p53 mutations in spontaneously immortalized 3T12 but not 3T3 mouse embryo cells Oncogene 7:935–942 Robanus Maandag EC, Van der Valk M, Vlaar M, Feltkamp C, O’Brien J, Van Roon M, Van der Lugt N, Berns A, Te Riele H (1994) Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice EMBO J 13:4260– 4268 Robanus-Maandag E, Dekker M, Van der Valk M, Carrozza ML, Jeanny JC, Dannenberg JH, Berns A, Te Riele H (1998) p107 is a suppressor of retinoblastoma development in pRb-deficient mice Genes Dev 12:1599–1609 Ross JF, Näär A, Cam H, Gregory R, Dynlacht D (2001) Active repression and E2F inhibition by pRB are biochemically distinguishable Genes Dev 15:392–397 Ruas M, Peters G (1998) The p16INK4A /CDKN2A tumor suppressor and its relatives Biochem Biophys Acta Rev Cancer 1378:F115–F177 Russell JL, Powers JT, Rounbehler RJ, Rogers PM, Conti CJ, Johnson DG (2002) ARF differentially modulates apoptosis induced by E2F1 and Myc Mol Cell Biol 22:1360– 1368 Ruiz S, Santos M, Segrelles C, Hugo L, Jorcano JL, Berns A, Paramio JM, Vooijs M (2004) Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis Development 131:2737–2748 Ryan RS, Gee R, O’Connell JX, Harris AC, Munk PL (2003) Leiomyosarcoma of the distal femur in a patient with a history of bilateral retinoblastoma: a case report and review of the literature Skeletal Radiol 32:476–480 Saenz-Rjobles MT, Symonds H, Chen J, Van Dyke T (1994) Induction versus progression of brain tumor development: differential functions for the pRB- and p53-targeting domains of simian virus 40 T antigen Mol Cell Biol 14:2686–2698 Sage C, Huang M, Karimi K, Gutierrez G, Vollrath MA, Zhang DS, Garcia-Anoveros J, Hinds PW, Corwin JT, Corey DP, Chen ZY (2005) Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein Science 307:1114–1118 222 J.-H Dannenberg · H.P.J te Riele Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theorou E, Jacks T (2000) Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization Genes Dev 14:3037–3050 Sage J, Miller AL, Perez-Mancera P, Wysocki JM, Jacks T (2003) Acute mutation of retinoblastoma gene function is sufficient for cell cycle entry Nature 424:223–228 Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002) A senescence program controlled by p53 and p16INK4A contributes to the outcome of cancer therapy Cell 109:335–346 Sellers WR, Novitch BG, Miyake S, Heith A, Otterson GA, Kaye FJ, Lassar AB, Kaelin WG (1998) Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth Genes Dev 12:95–106 Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 Nature 366:704–707 Serrano M, Lee HW, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4A locus in tumor suppression and cell mortality Cell 85:27–37 Serrano M, Lin AW, Mila EM, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16Ink4a Cell 88:593– 602 Schneider JW, Gu W, Zhu L, Mahdavi V, Nadal-Ginard B (1994) Reversal of terminal differentiation mediated by p107 in Rb–/– muscle cells Science 264:1467–1471 Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis Nature 413:86–91 Sherr CJ (1996) Cancer cell cycles Science 274:1672–1677 Sherr CJ (1998) Tumor surveillance by the ARF-p53 pathway Genes Dev 12:2984–2991 Sherr CJ (2001a) Parsing Ink4a/Arf: pure p16-null mice Cell 106:531–534 Sherr CJ (2001b) The Ink4a/ARF network in tumour suppression Nature Reviews Molecular Biology 2:731–737 Sherr CJ, DePinho RA (2000) Culture clock or culture shock? Cell 102:407–410 Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1 -phase progression Genes Dev 13:1501–1512 Slebos RJC, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB, Cho KR (1994) p53-dependent G1-arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein Proc Natl Acad Sci USA 91:5320–5324 Sotillo R, Dubus P, Martin J, de la Cueva E, Ortega S, Malumbres M, Barbacid M (2001) Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors EMBO J 20:6637–6647 Stanton SE, Shin SW, Johnson BE, Meyerson M (2000) Recurrent allelic deletions of chromosome arms 15q and 16q in human small cell lung carcinomas Genes, Chrom Cancer 27:323–331 Starostik P, Chow KN, Dean DC (1996) Transcriptional repression and growth suppression by the p107 pocket protein Mol Cell Biol 16:3606–3614 Steele-Perkins G, Fang W, Yang XH, Van Gele M, Carling T, Gu J, Buyse IM, Fletcher JA, Liu J, Bronson R, Chadwick RB, de la Chapelle A, Zhan X, Speleman F, Huang S (2001) Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily Genes Dev 15:2250–2262 Stiewe T, Pützer BM (2000) Role of the p53-homologue p73 in E2F1-induced apoptosis Nat Genet 26:464–469 The Retinoblastoma Gene Family 223 Strachan GD, Rallapalli R, Pucci B, Toulouse PL, Hall DJ (2001) A transcriptionally inactive E2F-1 targets the MDM family of proteins for proteolytic degradation J Biol Chem 276:45677–45685 Sun P, Dong P, Dai K, Hannon GJ, Beach D (1998) p53-independent role of MDM2 in TGFbeta1 resistance Science 282:2270–2272 Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T, Van Dyke T (1994) p53dependent apoptosis suppresses tumor growth and progression in vivo Cell 78:703–711 Tajima Y, Munakata S, Ishida Y, Nakajima T, Sugano I, Nagao K, Minoa K, Kondo Y (1994) Photoreceptor differentiation of retinoblastoma: an electron microscopic study of 29 retinoblastomas Pathol Int 44:837–843 Takahashi Y, Rayman JB, Dynlacht BD (2000) Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression Genes Dev 14:804–816 T’Ang A, Varley JM, Chakraborty S, Murphree AL, Fung YK (1988) Structural rearrangement of the retinoblastoma gene in human breast carcinoma Science 242:263–266 Tang DG, Tokumoto YM, Apperly JA, Lloyd AC, Raff MC (2001) Lack of replicative senescence in cultured rat oligodendrocyte precursor cells Science 291:868–871 Te Riele H, Robanus-Maandag E, Berns A (1992) Highly efficient gene targeting in embryonic stem cells through homologous recombination with isogenic DNA constructs Proc Natl Acad Sci USA 89:5128–5132 Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW (2001) The retinoblastoma protein acts as a transcriptional co-activator required for osteogenic differentiation Mol Cell 8:303–316 Todaro GJ, Green H (1963) Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines J Cell Biol 17:299–313 Tolbert D, Lu X, Yin C, Tantama M, Van Dyke T (2002) p19ARF is dispensable for oncogenic stress-induced p53-mediated apoptosis and tumor suppression in vivo Mol Cell Biol 22:370–377 Tonks ID, Hacker E, Irwin N, Muller HK, Keith P, Mould A, Zournazi A, Pavey S, Hayward NK, Walker G, Kay GF (2005) Melanocytes in conditional Rb-/- mice are normal in vivo but exhibit proliferation and pigmentation defects in vitro Pigment Cell Res 18:252–264 Trimarchi JM, Lees JA (2001) Sibling rivalry in the E2F family Nat Rev Mol Cell Biol 3:11–20 Trouche D, Le Chalony C, Muchardt C, Yaniv M, Kouzarides T (1997) RB and hBrm cooperate to repress the activation functions of E2F1 Proc Natl Acad Sci USA 94:11268– 11273 Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T (1998) Mutation of E2F-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos Mol Cell 2:293–304 Tsai KY, MacPherson D, Rubinson DA, Crowley D, Jacks T (2002) ARF is not required for apoptosis in Rb mutant mouse embryos Curr Biol 12:159–163 Uchida C, Miwa S, Kitagawa K, Hattori T, Isobe T, Otani S, Oda T, Sugimura H, Kamijo T, Ookawa K, Yasuda H, Kitagawa M (2005) Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation EMBO J 24:160–169 Verona R, Moberg K, Estes S, Starz M, Vernon JP, Lees JA (1997) E2F activity is regulated by cell cycle-dependent changes in subcellular localization Mol Cell Biol 17:7268–7282 Vooijs M, Berns A (1999) Developmental defects and tumor predisposition in Rb mutant mice Oncogene 18:5293–5303 Vooijs M, van der Valk M, Te Riele H, Berns A (1998) Flp-mediated tissue-specific inactivation of the retinoblastoma tumor suppressor gene in the mouse Oncogene 17:1–12 224 J.-H Dannenberg · H.P.J te Riele Vooijs M, Te Riele H, Van Der Valk M, Berns A (2002) Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinal binding protein-expressing cells Oncogene 21:4635–4645 Voorhoeve PM, Watson RJ, Farlie PG, Bernards R, Lam EWF (1998) Rapid dephosphorylation of p107 upon UV irradiation Oncogene 18:679–688 Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP (2000) p53-independent functions of the p19ARF tumor suppressor Genes Dev 14:2358–2365 Weinberg RA (1995) The retinoblastoma protein and cell cycle control Cell 81:323–330 Welch PJ, Wang JY (1993) A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle Cell 75:779–790 Wells J, Boyd KE, Fry CJ, Bartley SM, Farnham PJ (2000) Target gene specificity of E2F and pocket protein family members in living cells Mol Cell Biol 20:5797–5807 White E (1996) Life, death, and the pursuit of apoptosis Genes Dev 10:1–15 Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E (1988) Association between an oncogene and an anti-oncogene: The adenovirus E1A proteins bind to the retinoblastoma gene product Nature 334:124–129 Wiggan O, Taniguchi-Sidle A, Hamel PA (1998) Interaction of the pRB-family proteins with factors containing paired-like homeodomains Oncogene 16:227–236 Wikenheiser-Brokamp KA (2004) Rb family proteins differentially regulate distinct cell lineages during epithelial development Development 131:4299–4310 Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T (1994a) Cooperative tumorigenic effects of germline mutations in Rb and p53 Nat Genet 7:480–484 Williams BO, Schmitt EM, Remington L, Bronson RT, Jacks T (1994b) Extensive contribution of Rb-deficient cell to adult chimeric mice with limited histopathological consequences EMBO J 13:4251–4259 Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolis F, Giangrande P, Wright FA, Field SJ, Greenberg M, Orkin S, Nevins JR, Robinson ML, Leone G (2001) The E2F1-3 transcription factors are essential for cellular proliferation Nature 414:457–461 Wu L, de Bruin A, Saavedra HI, Starovic M, Trimboli A, Yang Y, Opavska J, Wilson P, Thompson JC, Ostrowski MC, Rosol TJ, Woollett LA, Weinstein M, Cross JC, Robinson ML, Leone G (2003) Extra-embryonic function of Rb is essential for embryonic development and viability Nature 421:942–947 Xiao Z, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR, Livingston DM (1995) Interaction between the retinoblastoma protein and the oncoprotein MDM2 Nature 375:694–698 Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E, Jacks T (1998) Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/–) mice Nat Genet 18:360–364 Yeung RS, Bell DW, Testa JR, Mayol X, Baldi A, Graña X, Klinga-Levan K, Knudson AG, Giordano A (1993) The retinoblastoma-related gene, Rb2, maps to a human chromosome 16q12 and rat chromosome 19 Oncogene 8:3465–3468 Yin C, Knudson CM, Korsmeyers JS, Van Dyke T (1997) Bax suppresses tumorigenesis and stimulates apoptosis in vivo Nature 385:637–640 Zamanian M, La TN (1993) Transcriptional repression by the Rb-related protein p107 Mol Biol Cell 4:389–396 Zacksenhaus E, Jiang Z, Chung D, Marth JD, Phillips RA, Gallie BL (1996) pRb controls proliferation, differentiation and death of skeletal muscle cells and other lineages during embryogenesis Genes Dev 10:3051–3064 The Retinoblastoma Gene Family 225 Zacksenhaus E, Jiang Z, Hei YJ, Philips RA, Gallie B (1999) Nuclear localization conferred by the pocket domain of the retinoblastoma gene product Biochim Biophys Acta 1451:288–296 Zhang HS, Postigo AA, Dean DC (1999) Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4A , TGFβ, and contact inhibition Cell 97:53–61 Zhang J, Schweers B, Dyer MA (2004) The first knockout mouse model of retinoblastoma Cell Cycle 3:952–959 Zhang S, Ramsay ES, Mock B (1998a) Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16INK4A and p19ARF , is a candidate for the plasmacytoma susceptibility locus, Pctr1 Proc Natl Acad Sci USA 95:2429–2434 Zhang Y, Xiong Y, Yarbrough WG (1998b) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4A locus deletion impairs both the Rb and p53 tumor suppression pathways Cell 92:725–734 Zhu L, Van den Heuvel S, Helin K, Fattaey A, Ewen M, Livingston DM, Dyson N, Harlow E (1993) Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein Genes Dev 7:1111–1125 Ziebold U, Reza T, Caron A, Lees JA (2001) E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos Genes Dev 15:386–391 Zindy F, Quelle DE, Roussel MF, Sherr CJ (1997) Expression of the p16INK4A tumor suppressor versus other INK4 family members during mouse development and aging Oncogene 15:203–211 Zindy F, Eischen CM, Randle D, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization Genes Dev 12:2424–2433 Zou X, Ray D, Aziyu A, Christov K, Boiko AD, Gudkov AV, Kiyokawa H (2002) Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence Genes Dev 16:2923–2934 ... on the role of the retinoblastoma gene family in cell cycle regulation and tumor suppression The pRb Cell Cycle Control Pathway: Components and the Cancer Connection The retinoblastoma protein,... over-expression of D-type cyclins, mutations rendering Cdk4 The Retinoblastoma Gene Family 185 Fig The p16INK4A -pRb and the p19ARF -p53 pathway involved in cell cycle progression and tumorigenesis Components... will be used The Retinoblastoma Gene Family 187 The Retinoblastoma Gene Family 4.1 Rb Gene Family Members The retinoblastoma gene family comprises, besides Rb, the structurally and functionally

Ngày đăng: 25/10/2013, 21:20

Từ khóa liên quan

Tài liệu cùng người dùng

  • Đang cập nhật ...

Tài liệu liên quan